PhD topic / PhD position: Prioritizing drug combinations in leukemia based on analysis of targetted therapy in vivo

Supervisor: Miroslav Boudny

Consultant: Marek Mraz

Annotation: We are looking for a motivated PhD student that would like to work on the following project funded by the ERC (European Research Council) Starting grant. The variable clinical course of several B cell malignancies largely depends on p53 functionality and B-cell receptor (BCR) signalling propensity; however, it is unclear if there is any crosstalk between these pathways. We showed for the first time that there is a connection between p53 pathway and regulation of BCR signaling (Cerna et al…Mraz, Leukemia, 2018). We described that DNA damage response (DDR) activation leads to down-modulating the transcriptional factor FOXP1, which functions as a positive BCR signalling. It seems that the low FOXP1 levels limit BCR signalling partially via allowing for upregulation of a CD22 cell-surface, whose intracellular part serves as a docking site for phosphatases that limit BCR activation on the cell membrane. The student will further explore the connection between DNA damage response and the BCR signalling regulation. Additionally, the p53 aberration could also affect the basal levels of CD22/phosphatases, and thus contribute to the “tonic” BCR signalling, and general aggressiveness of the B cells. In vitro studies using Crispr technology and inducible shRNAs for p53 will be conducted. Additionally, we have collected over 100 samples obtained during the administration of chemo-immuno therapy in B-cell chronic lymphocytic leukaemia (CLL) patients, and these can be used to validate the in vitro observations.

Recommended literature:

• Cerna K, Oppelt J, Chochola V, Musilova K, Seda V, Pavlasova G, Radova L, Arigoni M, Calogero RA, Benes V, Trbusek M, Brychtova Y, Doubek M, Mayer J, Pospisilova S, Mraz M. MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells. Leukemia. 2019 Feb;33(2):403-414. doi: 10.1038/s41375-018-0230-x. Epub 2018 Aug 15. PMID: 30111844
• Cerna K, Mraz M. p53 limits B cell receptor (BCR) signalling: a new role for miR-34a and FOXP1. Oncotarget. 2018 Nov 23;9(92):36409-36410
• Kipps et al. Chronic lymphocytic leukaemia. Nat Rev 2017 https://pubmed.ncbi.nlm.nih.gov/28102226/

Requirements on candidates:

Motivated smart people that have the “drive” to work independently, but also willing to learn from other people in the lab and collaborate. Candidates should have a master’s degree in Molecular biology, Biochemistry, or similar field and have deep interest in molecular biology and cancer cell biology.

More information on CEITEC PhD School website: https://ls-phd.ceitec.cz/ and Research Group website: https://www.ceitec.eu/microenvironment-of-immune-cells/rg115. 

In case you are interested. ​Please, submit your CV and motivation letter via Registration Form.

Listen to the experiences of our PhD students:

·         Cosimo Lobello – Medical Genomics Group

·         Abigail Rubiato Cuyacot – Functional Genomics and Proteomics of Plants Group

·         Karel Škubník – Structural Virology Group